This invention is in the field of antiviral agents and specifically relates to compounds, compositions and methods for treating herpesvirus infections.
There is a great need for new therapies active in the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of herpesvirus. ganciclovir, aciclovir and foscarnet are currently utilized for the treatment of herpesvirus infections, however, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication. They also affect a limited number of viral infections. In addition, viruses are known to develop resistance to therapies, and such resistance causes a progressive decline in efficacy.
Viruses are classified into broad categories based on whether they incorporate RNA or DNA. Important virus families classified of RNA type include orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronaviridae, togaviridae, bunyaviridae, arenaviridae and retroviridae. Important virus families classified of DNA type include adenoviridae, poxviridae, papovaviridae and herpesviridae.
Herpesviridae is a family of DNA viruses which include herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
It is known that herpesvirus replicate by directing the synthesis of a number of proteins encoded by the herpesvirus DNA in the host cell. One of the important virus-encoded proteins is made as a fusion protein precursor consisting of an amino terminal-located protease and carboxyl terminal-located capsid assembly protein. This precursor is proteolytically processed in an autocatalytic manner at a specific amino acid sequence known as the xe2x80x9creleasexe2x80x9d site, yielding separate protease and capsid assembly protein. The capsid assembly protein is cleaved further by the protease at another specific amino acid sequence known as the xe2x80x9cmaturationxe2x80x9d cleavage site. U.S. Pat. No. 5,478,727, to Roizman and Liu, describes a virus-specific serine protease which has a role in HSV replication. Liu and Roizman [J. Virol, 65, 5149 (1991)] describe the sequence and activity of a protease and the associated assembly protein encoded by UL26 of HSV-1. Recently, U.S. Pat. No. 5,434,074, to W. Gibson and A. Welch, describes a simian CMV protease. A. Welch et al. [Proc. Natl. Acad. Sci. USA, 88, 10792 (1991)] describe the related protease (also known as assemblin) and assembly protein encoded by UL80 of a human CMV. An approach currently being investigated for potential use in the treatment of herpesvirus infections is the development of inhibitors of herpesvirus proteases.
Arylketones containing a tetrazolylcarbonylamino substituent have been described. European publication EP 337,701, published Apr. 11, 1988, describes the use of 3-acetyl-5-fluoro-2-hydroxytetrazole-5-carboxanilide for treating autoimmune disorders or arthritis.
Substituted arylureas have been described in European publication EP 355,819, published Feb. 28, 1990, as high intensity sweeteners.
Aryltrihalomethylketones combined with hydrogen peroxide have been described in European patent publication EP 298,020, published Jan. 4, 1989, as reagents for epoxidation of steroids. German patent document DE 4,201,435, describes a method of preparing trifluoromethylketones from the alcohols.
U.S. Pat. No. 4,855,460, to M. Tordeux et al., describes the formation of simple pseudoacids via perfluoroalkylation of acid anhydrides. Specifically, trifluoroacetophenone is described.
WO 92/18475, published Oct. 29, 1992, describes phenylsubstituted pyrrolidines as dopamine receptor agonist/antagonists. Aryltrifluoromethylcarbinols have been described in U.S. Pat. No. 4,285,943, issued to M. Vincent et al., as analgesic, antipyretic, and anti-inflammatory agents.
Inhibition of serine proteases by electrophilic carbonyl derivatives, in particular peptidyl derivatives possessing an electrophilic carbonyl or boron group, is a well documented process. Early work describes where the P1 cleavage site is mimicked by an electrophilic aldehyde, alpha-ketoester, trifluoromethylketone, alphaketoamide, or boronic ester. [See J. Powers and J. Wade Harper, xe2x80x9cInhibitors of Serine Proteasesxe2x80x9d, in Proteinase Inhibitors, 55-152 (1986); R. Wiley and D. Rich, Medicinal Research Reviews, 13, 327-384 (1993).]
For example, the compounds in European patent publication EP 276,101, published Jul. 27, 1988, are described as inhibiting human leukocyte elastase (HLE). Generally, the inhibitors consist of a proline-based peptidyl sequence which is terminated by a trifluoromethylketone. European publication EP 249,349, published Dec. 16, 1987, describes a proline-derived peptide sequence terminated by a 2,2-difluoro-3-phenyl-1,3-dicarbonyl group. European publication EP 204,571, published Dec. 12, 1986, describes a proline-derived peptide sequence consisting of one-three amino acids and terminated by a 2,2-difluoro-3-phenyl-1,3-dicarbonyl group.
Several references have described aryltrifluoromethylketones as inhibitors of acetylcholinesterase, a serine esterase. European publication EP 403,713, published Dec. 27, 1990, describes m-(silyl)phenylfluoroketones in treatment of Alzheimers disease and senile dementia. U.S. Pat. No. 5,166,181 describes [m-(alkylaminoalkyl)aryl]-haloketone compounds as acetylcholinesterase inhibitors. Specifically, 1-[3-[1-(N,N-dimethylamino)ethyl]phenyl]-2,2,2-trifluoroethanone is described.
Halosubstituted acetophenones have not previously been described as selective herpesvirus protease inhibitors or for the treatment and/or prophylaxis of herpesvirus infection.
The present invention relates to a class of halo-substituted acetophenones, useful in the therapeutic and prophylactic treatment of viral infections, as defined by Formula I: 
wherein each of R1, R2, R3, and R4 is independently selected from hydrido, alkyl, aralkyl, halo, alkoxy, cyano, nitro, amino, alkylamino, N-acylamino, alkylsulfonyloxy, aminosulfonyl, N-(haloalkylcarbonyl)amino, peptidyl, amino acid residue, 
wherein R5 is selected from alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, alkylamino, arylamino, aralkylamino, alkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl, wherein R5 is optionally substituted at a substitutable position with one or more substituents selected from alkyl, alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, N-acylamino, amino, alkylamino, alkoxycarbonyl, amino acid residue and peptidyl;
wherein R6 is selected from alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl, wherein R6 is optionally substituted at a substitutable position with a radical selected from alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, N-acylamino, amino, alkylamino and alkoxycarbonyl;
wherein Y is selected from fluoroalkyl and 
wherein Q is selected from alkoxy, aryloxy, aralkyloxy, amino acid residue, peptidyl, and xe2x80x94NHR7; and
wherein R7 is a radical selected from alkyl, aralkyl, and heterocyclylalkyl, wherein R7 is optionally substituted at a substitutable position with a radical selected from amino, nitrogen-containing heterocyclyl and alkylamino;
or a pharmaceutically-acceptable salt or tautomer thereof.
The compounds of this invention have been shown to be particularly effective against herpetoviridae. Thus they are particularly useful for the treatment of herpes simplex viruses (HSV-1, HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr (EBV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
The invention further involves a method of treating a subject having a viral infection with an effective amount of a compound of Formula I. Preferably, the subject is treated with a herpesvirus protease inhibitor. More preferred is a method wherein the viral protease inhibitor is a CMV protease inhibitor, EBV protease, VZV protease or an HSV protease inhibitor. Even more preferred is a method wherein the subject is treated with an inhibitor of CMV protease, encoded by UL80, HSV-1 protease or HSV-2 protease encoded by UL26, such as the halosubstituted acetophenone compounds of the present invention.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of animals, including companion animals and farm animals, such as, but not limited to, horses, dogs, cats, cows, fish, sheep and pigs.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiviral compounds, such as together with antivirals including but not limited to ganciclovir, docosanol, trifluridine, foscarnet, ribavirin, epervudine, interferon, thymostimulin, Ciba-Geigy CGP-16056, sprofen, Efalith, ibuprofen piconol, ufenamate, thymopentin, aciclovir, valaciclovir, edoxudine, famciclovir, idoxuridine, vidarabine, Epavir, zinc acetate, tromantadine, riodoxol, sorivudine, Yakult Honsha LC-9018, cidofovir, bromovinyldeoxyuridine, Lidakol, Stega Pharmaceutical cytokine-releasing agent, CSL ISCOM, penciclovir, Viraplex, Pharmacia and Upjohn THF, Boehringer Ingelheim BIRR-4, NIH peptide T, Virend, zinc glycerolate, and lobucavir.
A preferred class of compounds consists of those compounds of Formula I wherein each of R1, R2, R3, and R4 is independently selected from hydrido, lower alkyl, lower aralkyl, halo, lower alkoxy, cyano, nitro, amino, lower alkylamino, N-acylamino, lower alkylsulfonyloxy, aminosulfonyl, lower N-(haloalkylcarbonyl)amino, amino acid residue, peptidyl, 
wherein R5 is selected from lower alkoxy, phenyloxy, lower aralkyloxy, lower alkylthio, phenylthio, lower aralkylthio, lower alkylamino, arylamino, lower aralkylamino, lower alkyl, 6-10-membered aryl, lower aralkyl, 5-10-membered heterocyclyl, and lower heterocyclylalkyl, wherein R5 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, lower alkoxy, phenyloxy, lower alkylthio, phenylthio, halo, nitro, N-acylamino, amino, lower alkylamino, lower alkoxycarbonyl, amino acid residue and peptidyl; wherein R6 is selected from lower alkyl, 6-10-membered aryl, lower aralkyl, 5-10-membered heterocyclyl and lower heteroaralkyl, wherein R6 is optionally substituted at a substitutable position with a radical selected from lower alkoxy, phenyloxy, lower alkylthio, phenylthio, halo, nitro, N-acylamino, amino, lower alkylamino, and lower alkoxycarbonyl; wherein Y is selected from lower fluoroalkyl and 
wherein Q is selected from lower alkoxy, phenyloxy, lower aralkyloxy, N-amino acid residue, N-peptidyl, and xe2x80x94NHR7; and wherein R7 is a radical selected from lower alkyl, lower aralkyl, and lower heteroaralkyl, wherein R7 is optionally substituted at a substitutable position with one or more radical selected from amino, 5-6-membered nitrogen-containing heterocyclyl and lower N,N-dialkylamino; or a pharmaceutically-acceptable salt or tautomer thereof.
A more preferred class of compounds consists of those compounds of Formula I wherein Y is lower fluoroalkyl; wherein each of R1, R2, R3, and R4 is independently selected from hydrido, lower alkyl, halo, lower alkoxy, nitro, and amino; and wherein R5 is selected from phenylalkoxy, lower alkyl substituted with halo or phenyloxy, phenyl, lower phenylalkyl, and five-ten membered heteroaryl, wherein R5 is optionally substituted at a substitutable position of a phenyl or heteroaryl radical with one or more substituents selected from lower alkyl, lower alkoxy, phenyloxy, lower alkylthio, phenylthio, halo, nitro, N-acylamino, amino, lower alkylamino, lower alkoxycarbonyl, amino acid residue, and peptidyl; or a pharmaceutically-acceptable salt or tautomer thereof.
An even more preferred class of compounds consists of those compounds of Formula I wherein Y is selected from difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, 1,1-difluoroethyl, and 1,1-difluoropropyl; wherein each of R1, R2, R3, and R4 is independently selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, nitro, and amino; wherein R5 is selected from phenylmethoxy, phenylethoxy, phenylpropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, phenyloxyethyl, phenyloxypropyl, phenyl, phenylmethyl, phenylethyl, furyl, pyrazinyl, oxazolyl, thiazolyl, thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, and pyridyl, wherein R5 is optionally substituted at a substitutable position of a phenyl or heteroaryl radical with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, phenyloxy, methylthio, phenylthio, fluoro, chloro, bromo, iodo, nitro, N-formylamino, acetylamino, amino, N,N-dimethylamino and methoxycarbonyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Another more preferred class of compounds consists of those compounds of Formula I wherein Y is 
wherein Q is selected from lower alkoxy, phenyloxy, lower aralkyloxy, N-amino acid residue, N-peptidyl, and xe2x80x94NHR7; and wherein R7 is a radical selected from lower alkyl, lower aralkyl, and lower heteroaralkyl, wherein R7 is optionally substituted at a substitutable position with a radical selected from amino, 5-6 membered nitrogen-containing heterocyclyl and lower N,N-dialkylamino; wherein each of R1, R2, R3, and R4 is independently selected from hydrido, lower alkyl, halo, lower alkoxy, nitro, and amino; and wherein R5 is selected from phenylalkoxy, lower alkyl substituted with halo or phenyloxy, phenyl, lower phenylalkyl, and five-ten membered heteroaryl, wherein R5 is optionally substituted at a substitutable position of a phenyl or heteroaryl radical with one or more substituents selected from lower alkyl, lower alkoxy, phenyloxy, lower alkylthio, phenylthio, halo, nitro, N-acylamino, amino, lower alkylamino, lower alkoxycarbonyl, amino acid residue, and peptidyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Another even more preferred class of compounds consists of those compounds of Formula I wherein Y is 
wherein Q is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, phenyloxy, benzyloxy, phenylethoxy, and xe2x80x94NHR7; and wherein R7 is a radical selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, benzyl, phenethyl, oxazolylmethyl, oxazolylethyl, imidazolylmethyl, imidazolylethyl, oxazolinylmethyl, oxazolinylethyl, indolylethyl, indolylmethyl, pyridylmethyl, thienylmethyl, and furylethyl, wherein R7 is optionally substituted at a substitutable position with a radical selected from amino, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidyl and N,N-dimethylamino; wherein each of R1, R2, R3, and R4 is independently selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, nitro, and amino; and wherein R5 is selected from phenylmethoxy, phenylethoxy, phenylpropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, phenyloxyethyl, phenyloxypropyl, phenyl, phenylmethyl, phenylethyl, furyl, pyrazinyl, oxazolyl, thiazolyl, thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, and pyridyl, wherein R5 is optionally substituted at a substitutable position on a phenyl or heteroaryl radical with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, tert-butoxy, phenyloxy, methylthio, phenylthio, fluoro, chloro, bromo, iodo, nitro, N-formylamino, N-acetylamino, amino, N,N-dimethylamino and methoxycarbonyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Another preferred class of compounds consists of those compounds of Formula II wherein 
wherein each of R1, R2, and R3 is independently selected from hydrido, halo, and nitro;
wherein R8 is selected from haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted arylalkoxy and optionally substituted aryloxyalkyl;
wherein Y is selected from fluoroalkyl, and 
and
wherein R9 is alkylamino;
or a pharmaceutically-acceptable salt or tautomer thereof.
Another preferred class of compounds consists of those compounds of Formula II wherein R1 is selected from hydrido, fluoro, chloro, bromo and iodo; wherein R2 is selected from hydrido, fluoro, chloro, bromo and iodo; wherein R3 is selected from hydrido, fluoro, chloro, bromo, iodo and nitro; wherein R8 is selected from trifluoromethyl, phenyl, phenylmethyl, phenylethyl, furyl, pyridyl, pyrazinyl, thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, phenylmethyloxy, (phenyloxy)propyl and phenyloxymethyl; wherein Y is selected from trifluoromethyl and 
and
wherein R9 is selected from methylamino, ethylamino, propylamino, isopropylamino and N,N-dimethylamino; or a pharmaceutically-acceptable salt or tautomer thereof.
A family of specific compounds of particular interest within Formulas I and II consists of compounds and pharmaceutically-acceptable salts thereof as follows:
xcex1-phenoxy-N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]butanamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]furan-2-carboxamide;
N-[5-fluoro-2-(2,2,2-trifluoro-1-oxoethyl)phenyl]benzenepropanamide;
N-[3-chloro-2-(2,2,2-trifluoro-1-oxoethyl)phenyl]benzenepropanamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]benzenepropanamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]pyrazine-2-carboxamide;
phenylmethyl N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]carbamate;
N-[5-nitro-2-[2,2,2-trifluoro-1-oxoethyl)phenyl]benzenepropanamide;
N-[4-fluoro-2-(2,2,2-trifluoro-1-oxoethyl)phenyl]furan-2-carboxamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]-1-benzothiophene-2-carboxamide;
xcex1,xcex1,xcex1-trifluoro-N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]acetamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]pyridine-2-carboxamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]2-methoxybenzamide;
N-[4-iodo-2-(2,2,2-trifluoro-1-oxoethyl)phenyl]furan-2-carboxamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]4-chlorophenoxyacetamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]indolyl-2-carboxamide;
N-[2-(2,2,2-trifluoro-1-oxoethyl)phenyl]benzofuranyl-2-carboxamide; and
N-[2-(3-(2-propylamino)-3-oxo-2,2-difluoro-1-oxopropyl)phenyl]2-methoxyphenylcarboxamide.
As illustrated, the interconverting tautomers of Formula I (I and Ixe2x80x2) are encompassed within the scope of the present invention 
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical. Where used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, and xe2x80x9caralkylxe2x80x9d the term xe2x80x9calkylxe2x80x9d embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine. The term xe2x80x9cfluoroalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with fluoro atoms. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more fluoro atoms. xe2x80x9cLower fluoroalkylxe2x80x9d embraces radicals having 1-6 carbon atoms. Examples of fluoroalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, 1,1-difluoroethyl, and 1,1-difluoropropyl. The term xe2x80x9calkoxyxe2x80x9d embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, acylamino, peptidyl, amino, halo, nitro, alkoxycarbonyl and aralkoxycarbonyl. The terms xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d embrace saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 5 to 7-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tropanyl, homotropanyl, etc.]; saturated 5 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 5 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, oxazolinyl, pyrrolinyl, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed xe2x80x9cheteroarylxe2x80x9d radicals include unsaturated 5 to 7 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, azepinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; unsaturated 5 to 7-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 5 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term heteroaryl also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuryl, benzothienyl, and the like. Said xe2x80x9cheterocyclylxe2x80x9d radicals may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, acylamino, peptidyl, amino, halo, nitro, alkoxycarbonyl and aralkoxycarbonyl. More preferred heteroaryl radicals include five to six membered heteroaryl radicals. The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term xe2x80x9carylthioxe2x80x9d embraces radicals containing an aryl radical, of six to about ten carbon atoms attached to a divalent sulfur atom. Examples of such arylthio radicals are phenylthio, and naphthylthio. The term xe2x80x9caralkylthioxe2x80x9d embraces radicals containing an aralkyl radical attached to a divalent sulfur atom. More preferred aralkylthio radicals are xe2x80x9clower aralkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower aralkylthio radicals are benzylthio and phenylethylthio. The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The terms xe2x80x9csulfamylxe2x80x9d, xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidylxe2x80x9d denotes NH2O2Sxe2x80x94. The term xe2x80x9cacylxe2x80x9d denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include formyl, alkanoyl and aroyl radicals. The alkanoyl radicals may be substituted or unsubstituted, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which the preferable one is formyl, acetyl, propionyl or trifluoroacetyl. xe2x80x9cAlkylsulfonyloxyxe2x80x9d embraces alkylsulfonyl radicals attached to an oxygen atom, where alkylsulfonyl is defined above. More preferred alkylsulfonyloxy radicals are xe2x80x9clower alkylsulfonyloxyxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyloxy radicals include methylsulfonyloxy, and ethylsulfonyloxy. The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9calkoxycarbonylxe2x80x9d, denotes xe2x80x94(Cxe2x95x90O)xe2x80x94. The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Preferably, xe2x80x9clower alkoxycarbonylxe2x80x9d embraces alkoxy radicals having one to six carbon atoms. Examples of such xe2x80x9clower alkoxycarbonylxe2x80x9d ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Preferably, xe2x80x9clower alkoxycarbonylxe2x80x9d embraces alkoxy radicals having one to six carbon atoms. Examples of such xe2x80x9clower alkoxycarbonylxe2x80x9d ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may be additionally substituted as described above. The terms benzyl and phenylmethyl are interchangeable. The term xe2x80x9caralkoxycarbonylxe2x80x9d means a radical containing an aralkoxy radical, as defined below, attached via an oxygen atom to a carbonyl radical. Preferably, xe2x80x9clower aralkoxycarbonylxe2x80x9d embraces alkoxy radicals having one to six carbon atoms. Examples of such xe2x80x9clower aralkoxycarbonylxe2x80x9d ester radicals include substituted or unsubstituted benzyloxycarbonyl. The term xe2x80x9chaloalkylcarbonylxe2x80x9d embraces radicals having a haloalkyl radical as described above attached to a carbonyl radical. More preferred radicals are xe2x80x9clower haloalkylcarbonylxe2x80x9d radicals where lower haloalkyl radicals, as described above are attached to a carbonyl radical. The term xe2x80x9cheterocyclylalkylxe2x80x9d embraces heterocyclyl-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are xe2x80x9clower heterocyclylalkylxe2x80x9d radicals having five to ten membered heterocyclyl radicals attached to lower alkyl radicals having one to six carbon atoms. Examples of such radicals include oxazolylmethyl, oxazolylethyl, imidazolylmethyl, imidazolylethyl, oxazolinylmethyl, oxazolinylethyl, indolylethyl, indolylmethyl, pyridylmethyl, thienylmethyl, and furylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted as described above. The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals, as defined above, attached to an oxygen atom. The aryl in said aryloxy may be additionally substituted as described above. Examples of such radicals include phenoxy. The terms xe2x80x9caralkyloxyxe2x80x9d and xe2x80x9caralkoxyxe2x80x9d embrace oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkyloxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having phenyl radicals attached alkoxy radicals having one to six carbon atoms. Examples include benzyloxy and phenylethoxy. The xe2x80x9caralkoxyxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The term xe2x80x9caryloxyalkylxe2x80x9d embraces alkyl radicals having one or more aryloxy radicals attached to the alkyl radical, that is, to form monoaryloxyalkyl and diaryloxyalkyl radicals. The more preferred aryloxyalkyl radicals are xe2x80x9clower aryloxyalkylxe2x80x9d radicals having aryloxy radicals attached to one to six carbon atoms. Examples include phenoxymethyl and phenoxypropyl. The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two alkyl radicals. More preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d having alkyl radicals of one to six carbon atoms attached to the nitrogen atom of an amine. Suitable xe2x80x9clower alkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term xe2x80x9carylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The term xe2x80x9caralkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aralkyl radicals, such as N-benzylamino. The xe2x80x9caralkylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The term xe2x80x9cacylaminoxe2x80x9d denotes amino groups which have been substituted, through the carbonyl carbon, with one or two acyl radicals. Suitable xe2x80x9cacylaminoxe2x80x9d may be mono or diacylamino such as N-formylamino, N-acetylamino, or the like. The term xe2x80x9c(haloalkylcarbonyl)aminoxe2x80x9d denotes amino groups which have been substituted, through the carbonyl carbon, with one or two haloalkylcarbonyl radicals, as defined above. Suitable xe2x80x9c(haloalkylcarbonyl)aminoxe2x80x9d may be mono(haloalkylcarbonyl)amino such as N-trifluoromethylcarbonylamino, or the like. xe2x80x9cAmino acid residuexe2x80x9d means any of the naturally occurring alpha-, beta- and gamma-amino carboxylic acids, including their D and L optical isomers and racemic mixtures thereof, synthetic amino acids, and derivatives of these natural and synthetic amino acids. The amino acid residue is bonded either through an amino or an acid functional group of the amino acid. The naturally occurring amino acids which can be incorporated in the present invention include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, cyclohexylalanine, tryptophan, tyrosine, valine, xcex2-alanine, and xcex3-aminobutyric acid. Derivatives of amino acids which can be incorporated in the present invention include, but are not limited to amino acids having protected and modified carboxylic acids, including acid esters and amides, protected amines, and substituted phenyl rings, including but not limited to alkyl, alkoxy and halo substituted tyrosine and phenylalanine. The term xe2x80x9cpeptidylxe2x80x9d denotes a radical having two or three naturally occurring amino acids residues attached together through amide linkages. When the amino acid residue or peptidyl radical is attached from its N-amino terminus, such residues are noted as N-amino acid residue and N-peptidyl, respectively.
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a method of therapeutic and prophylactic treatment of a herpesvirus infection, in a subject, the method comprising administering to the subject having such herpes infection a therapeutically-effective amount of a compound of Formula I.
Also included in the family of compounds of Formula I are the stereoisomers and tautomers thereof. Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. Accordingly, some of the compounds of this invention may be present in racemic mixtures which are also included in this invention. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting an amine functionality of precursors to compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate. Alternatively, diastereomeric derivatives can be prepared by reacting a carboxyl functionality of precursors to compounds of Formula I with an optically pure amine base. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, xcex2-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
The compounds of the invention can be synthesized from commercially available starting materials, according to the following procedures of Schemes I-IX, wherein the R1-R9 substituents are as defined for Formulas I-II, above, except where further noted. 
The antiviral agents of this invention can be prepared following the method shown in Scheme I. The antiviral agents 2 are obtained by oxidation of the corresponding alcohol 1, such as by treatment with periodinane (Dess Martin Reagent) [D. Dess and J. Martin, J. Amer. Chem. Soc., 113, 7277 (1991)], or with a modified Pfitzner-Moffatt reagent (DMSO/DCC) (A. Doherty, et al., J. Med. Chem., 35, 2 (1992)]. 
The alcohol 1 can be obtained as outlined in Scheme II. The ortho nitroarylcarbinol 3 can be reduced to the corresponding aniline derivative 4 by catalytic hydrogenation, such as by using palladium on carbon [Rylander, Hydrogenation Methods, Chap. 8, (1985)] or alternative methods (stannous chloride reduction or with the anionic hydride [HFe(CO)4]xe2x80x94]. See P. Gaus et al., Tetrahedron Letters, 29, 5083 (1988). The aniline carbinol derivative 4 can be diacylated with the appropriate acid chloride in high yield. The resulting ester amide 5 can be selectively cleaved at the ester moiety such as by (1) mild base treatment (e.g. hydroxide ion) which affords the alcohol 1, or by (2) an appropriate esterase. 
The ortho-nitroarylcarbinol 7 can be obtained, when Y=CF3 (p=0), by treatment of the corresponding aldehyde 6 with trifluoromethyltrimethylsilane (CF3-TMS) and catalytic tetrabutyl ammonium fluoride (TBAF) [Olah et al., J. Amer. Chem. Soc., 111, 393 (1989)]. Alternatively, homologous perfluoroalkyl anions (p=1-3), may be generated by using the appropriate fluoroiodoalkane and an organolithium under transmetaling conditions [J. Begue and D. Delpon, Tetrahedron, 47, 3207 (1991)]. 
The ortho-nitroarylcarbinol 9 can be obtained, when Y is a difluoroacetamido group, as outlined in Scheme IV. The corresponding aldehyde 6 can be reacted with a Reformatsky reagent prepared from an xcex1-bromo-xcex1,xcex1-difluoroacetylester [Fried et al., J. Amer. Chem. Soc., 114, 8464 (1992); Thaisrivongs et al., J. Med. Chem., 29, 2080 (1986)] to form ester 8. The ester 8 can be reacted directly with primary amines [H2NR7] to afford secondary amides 9 by heating in an appropriate solvent, such as DMF or THF. 
Alternatively, the ester 8 can be cleaved to the free acid 10 and coupled to a primary amine, such as H2NR7, amino acid residue or a peptide, using standard amino acid coupling conditions, for example DSC, DCC, EDC, or BOP, to form compound 9. See Bodansky, Principles of Peptide Synthesis, 1984.
An alternative sequence starts with a commercially available anthranilic acid 11 as outlined in Scheme VI. The carboxylic acid 11 is reduced to the benzyl alcohol 12, such as with borane/THF reagent [Brown and Korytnyk, J. Amer. Chem. Soc., 82, 3866 (1960)]. The benzyl alcohol 12 is diacylated to afford 13. Subsequent selective ester cleavage [see Scheme II] gives the alcohol 14. The alcohol 14 can be oxidized to the aldehyde 15 by known methods (e.g. Swern oxidationxe2x80x94oxalyl chloride, DMSO, triethylamine; or sulfur trioxide/pyridine). The aldehyde 15 can be reacted with nucleophiles (as shown in Scheme III or Scheme IV) to afford carbinol 1.
Several specific examples of antiviral agents obtained through the application of Schemes I-VI are illustrated in Schemes VII-IX. The antiviral agent compound 21 (Example 1) is obtained in five steps starting from ortho nitrobenzaldehyde 16 as shown in Scheme VII. The aldehyde 16 is reacted with TF3-TMS/TBAF to afford carbinol 17. Reduction of the nitro group gives the aniline 18. Bis-acylation of the anilinocarbinol derivative 18 is accomplished by treatment with two equivalents of 2-furoyl chloride to afford ester 19. The ester 19 is cleaved selectively over the amide by treatment with one equivalent of sodium hydroxide at room temperature to afford compound 20. The carbinol 20 is oxidized by treatment with periodinane to afford compound 21.
The antiviral agent compound 27 (Example 17) is obtained in six steps from ortho nitrobenzaldehyde 16 as outlined in Scheme VIII. In the first step, carbinol 22 is obtained through a Reformatsky reaction using ethyl bromodifluoroacetate and zinc. In the second step, amidolysis of the ethyl ester of 22 is accomplished by heating compound 22 in the presence of excess isopropylamine in THF to afford compound 23. The ortho-nitro group of compound 23 is reduced by hydrogenation to give the aniline 24. Diacylation of 24 with o-anisolyl chloride affords compound 25. The ester of compound 25 is selectively cleaved by treatment with one equivalent of sodium hydroxide to afford carbinol 26 which is oxidized by periodinane (Dess-Martin reagent) treatment to afford compound 27.
The antiviral agent compound 34 (Example 2) is obtained in six steps from 4-fluoro-2-aminobenzoic acid 28 as outlined in Scheme IX. In the first step, the benzoic acid 28 is reduced to the benzyl alcohol 29 by treatment with borane-THF. Compound 29 is diacylated with hydrocinnamoyl chloride to afford ester 30 which is selectively cleaved at the ester by treatment with one equivalent of sodium hydroxide at room temperature to afford compound 31. The benzyl alcohol of 31 is converted to the benzaldehyde 32 by Swern oxidation. Treatment of 32 with TF3-TMS/TBAF affords carbinol 33. Carbinol 33 is oxidized to ketone 34 by treatment with periodinane (Dess-Martin oxidation).
The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I-II. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated.
The following abbreviations are used:
EtOAcxe2x80x94ethyl acetate
HClxe2x80x94hydrochloric acid
DMSOxe2x80x94dimethylsulfoxide
CDCl3xe2x80x94deuterated chloroform
CHCl3xe2x80x94chloroform
Et2Oxe2x80x94diethyl ether
MgSO4xe2x80x94magnesium sulfate
NaHCO3xe2x80x94sodium bicarbonate
KHSO4xe2x80x94potassium hydrogen sulfate
Na2SO4xe2x80x94sodium sulfate
Na2S2O4xe2x80x94sodium thiosulfate
DMFxe2x80x94dimethylformamide
NaOHxe2x80x94sodium hydroxide
Pd/Cxe2x80x94palladium on carbon
DCCxe2x80x94dicyclohexylcarbodiimide
DSCxe2x80x94disuccinimidylcarbonate
BOPxe2x80x94benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
EDCxe2x80x941-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl
BOCxe2x80x94tert-butyloxycarbonyl
MeOHxe2x80x94methanol
EtOHxe2x80x94ethanol
CH2Cl2xe2x80x94methylene chloride
hxe2x80x94hour
minxe2x80x94minutes
THFxe2x80x94tetrahydrofuran
IRxe2x80x94infrared
MSxe2x80x94mass spectrum